(13) Smart Biomaterials - Theranostics 13-EB-101*Theranostics: Combined delivery of diagnostic and therapeutic agents. Multimeric polyspecific protein therapeutics are difficult to design and produce. The ability to link binding, effector, and imaging components together in a single molecule would be a significant advantage. We propose to develop unnatural amino acid- oligonucleotide technology (UAA-oligo) in order to precisely control formation of modular therapeutics and diagnostics. An unnatural amino acid engineered in a single position will allow site-specific coupling of an oligonucleotide. The oligonucleotide can then be hybridized to its complement which is conjugated to a second modular protein. The base-pairing rules of DNA will allow higher order heterodimers, trimers, tetramers, and other multimers to be produced. This strategy will allow diagnostic and therapeutic modules to be coupled in a single molecule to produce a "Theranostic". PUBLIC HEALTH RELEVANCE: The ability to create modular protein therapeutics, such that novel binding, effector, and diagnostic proteins can be combined in a single "theranostic" has considerable importance in medicine. Specifically, this proposal aims to create the platform for discovery of such molecules as well as for their facile construction. We will use oligonucleotides and unnatural amino acids to site specifically link two or more proteins together through the complementary base pairing of nucleic acids. Molecules that we create could simultaneously detect, bind, and kill tumor cells through imaging, binding, and toxin modules. This "lego" block assembly process will allow a vast array of combinatorial protein theranostic modules to be created and evaluated against a myriad of diseases.